Adiposity is a condition of having a significantly greater body weight than normal as a result of accumulation of neutral fats (triacylglycerol or triglyceride, hereinafter also referred to as TG) in fat cells due to continuous excess energy intake compared to energy consumption (Non-Patent Document 1). Adiposity leads to life-style related disease (e.g., hyperlipidemia, hypertriglyceridemia, diabetes, hypertension, and arteriosclerosis), cerebrovascular disorder, coronary artery disease, respiratory abnormality, lower back pain, knee osteoarthritis, gout, cholelithiasis, and so on. Adiposity with a complication of these diseases or adiposity which may later lead to such a complication is defined as obesity and treated as a disease.
Moreover, in recent years, obesity has been shown to be one of the major causes of a life-style related disease called metabolic syndrome (Non-Patent Document 2). It has been reported that in individuals with obesity, fatty acids and factors such as TNF-α are released from accumulated visceral fats, and induce insulin resistance in skeletal muscles, the liver, and fat tissue while facilitating the synthesis of neutral fats in the liver, resulting in hyperlipidemia. Furthermore, an increase in serum insulin concentration induced by the insulin resistance increases peripheral vascular resistance via increased renal reabsorption of Na ions and activation of sympathetic nerves, causing hypertension. Hyperlipidemia, diabetes, and hypertension caused by obesity are also thought to trigger angiopathy such as cerebrovascular disorder or coronary artery disease caused by arteriosclerosis, resulting in severe, life-threatening clinical conditions.
Currently, drug therapy has been practiced on obesity based on the provisions of each country, and centrally acting anorectics such as mazindol (Non-Patent Document 3) and sibutramine (Non-Patent Document 4) and lipid absorption inhibitors such as the pancreatic lipase inhibitor orlistat are prescribed mainly for the purpose of controlling calorie intake. These drugs offer low satisfaction with treatment, although achieving some therapeutic effects. The centrally acting anorectics have adverse effects such as dry mouth, constipation, gastric discomfort, and in some cases, auditory hallucination and visual hallucination. Orlistat (Non-Patent Document 5) may cause adverse effects in the gastrointestinal tract, such as diarrhea, incontinence, steatorrhea, and flatus. Accordingly, there is a need for the development of more potent drugs with fewer adverse effects. Under such circumstances, active research and development has been conducted with the aim of developing novel anti-obesity drugs, most of which are anorectics.
Animals and plants store lipids as insoluble TG and produce energy by catabolizing TG according to need. TG taken from food is hydrolyzed into free fatty acid and monoacylglycerol in the lumen of the small intestine by the action of bile acid and pancreatic lipase. Micelles composed of free fatty acid, monoacylglycerol, and bile acid are absorbed into small intestinal epithelial cells in which TG is then re-synthesized in the endoplasmic reticulum by the action of acyl-coenzyme A synthetase (hereinafter, referred to as ACS), acyl-coenzyme A: monoacylglycerol acyltransferase, and DGAT. TG is combined with phospholipid, cholesterol, and apolipoprotein and secreted in the form of chylomicron into the lymph vessels in the stomach and intestine. TG is then secreted into the blood through the lymphatic trunk and transferred to the periphery for use. On the other hand, TG is also synthesized in fat tissue from glycerol 3-phosphate and free fatty acid by the action of ACS, glycerol 3-phosphate acyltransferase, lysophosphatidic acid acyltransferase, and DGAT (Non-Patent Document 6). TG taken excessively is thus accumulated in fat tissue, resulting in obesity.
DGAT, an intracellular enzyme found in the endoplasmic reticulum, catalyzes the most important reaction in the final step in the pathway of TG synthesis. i.e., the reaction of transferring acyl groups of acyl-coenzyme A to the 3 position of 1,2-diacylglycerol (Non-Patent Documents 7 to 9). It has been reported that DGAT has two isozymes DGAT1 (Non-Patent Document 10) and DGAT2 (Non-Patent Document 11). Since DGAT1 and DGAT2 are highly expressed in the small intestine and fat tissue and in the liver and fat tissue, respectively, it is believed that DGAT1 is involved mainly in fat absorption from the small intestine and fat accumulation in fat tissue and DGAT2 is involved mainly in TG synthesis or VLDL (very low density lipoprotein) secretion in the liver and fat accumulation in fat tissue. Although the difference between the roles of DGAT1 and DGAT2 has not yet been fully elucidated, the association of DGAT with obesity, lipid metabolism, glucose metabolism, and the like has been suggested (Non-Patent Document 12). DGAT is a key enzyme of TG synthesis in gastrointestinal epithelial cells and fat tissue. Drugs which inhibit DGAT suppress the TG synthesis and thus suppress fat absorption in the gastrointestinal tract and fat accumulation in fat tissue. Accordingly, such drugs are expected to be useful as therapeutic or preventive agents for, for example, adiposity, obesity, hyperlipidemia, hypertriglyceridemia, lipidosis, insulin resistance syndrome, diabetes, nonalcoholic steatohepatitis, or hyperlipidemia, hypertriglyceridemia, lipidosis, insulin resistance syndrome, diabetes, nonalcoholic steatohepatitis, hypertension, arteriosclerosis, cerebrovascular disorder, or coronary artery disease caused by obesity (Non-Patent Documents 13 to 17).
Anorectics directly or indirectly regulate the system of appetite control, and their mechanisms of action are broadly classified into central and peripheral actions. The centrally acting anorectics directly suppress appetite through their action on the hypothalamic neuronal system containing the feeding and satiety centers or on the monoaminergic neuronal system in the brain regulating this hypothalamic neuronal system. On the other hand, the peripherally acting anorectics indirectly suppress appetite through their action on the mechanism of detecting and transmitting information on nutrition intake from diets or accumulation of excess energy.
In recent years, the mechanism has been increasingly evident, in which, for example, gastrointestinal hormone (CCK, GLP-1, PYY, etc.) (Non-Patent Document 18) secreted in close relation to the digestion and absorption of food, or leptin (Non-Patent Document 19) secreted from fat cells in response to the amount of energy accumulated (amount of fats) conveys hormonal or neuronal signals regulating appetites from the periphery to the central nervous system. Novel anorectics associated with these peripheral signals are expected to serve as more effective anti-obesity drugs with fewer adverse reactions.
Patent Document 1 discloses compounds structurally similar to compounds of the present invention. This document describes compounds comprising two substituted phenyl groups bound via urea and amide bonds or via urea and ester bonds with a tetrahydroisoquinoline ring, and use thereof as a DGAT inhibitor. Moreover, Patent Document 2 describes use of these compounds as a feeding suppressant. However, these patent documents merely disclose compounds wherein a nitrogen atom on the tetrahydroisoquinoline ring is substituted by a substituted phenyl group via an amide or ester bond. On the other hand, in the compounds of the present invention, a nitrogen atom on a tetrahydroisoquinoline ring is substituted by a substituted cycloalkyl or cycloalkenyl group via an ester bond or the like.
In addition, some compounds having a DGAT inhibitory effect are known. However, all differ from the compounds of the present invention in their structures (e.g., Patent Documents 3, 4, and 5 and Non-Patent Documents 20 to 24). Also, some compounds having a feeding suppressant effect are known. However, all differ from the compounds of the present invention in their structures (see e.g., Patent Documents 6 and 7).
Patent Document 1: US No. 2007/0249620
Patent Document 2: International Publication No. WO2007/074753 Pamphlet
Patent Document 3: Japanese Patent Laid-Open No. 2007-131584
Patent Document 4: International Publication No. WO2006/019020 Pamphlet
Patent Document 5: Japanese Patent Laid-Open No. 2002-306199
Patent Document 6: International Publication No. WO2005/072740 Pamphlet
Patent Document 7: EP No. 1411881
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